Epinephrine has been reported to both increase and decrease the toxicity of local anesthetics after systemic administration. Major variants among these reports include the species and the particular local anesthetic studied. The objective of this study is to determine the significance of the type of local anesthetic as a factor by testing the effect of epinephrine on the toxicity of three types of local anesthetics in the same animal model system. In addition, the effect of levonordefrin on local anesthetic toxicity will be compared to that of epinephrine. The basic experimental method will consist of intravenous injection into the tail vein of male mice. Increasing doses of procaine (an ester), lidocaine (an amide), or bupivacaine (a newer, long-acting amide) either alone or in combination with a fixed dose of epinephrine or levonordefrin will be injected and dose-lethality curves will be constructed from the percent of animals dying at each dose level. Potentiation or antagonism of toxicity by either vasoconstrictor should be evidenced by a significant decrease or increase, respectively, in the LD50 of the local anesthetic. The LD50 and its confidence limits will be calculated by probit analysis of the dose-lethality curves. The relationship of vasoconstrictor dosage to local anesthetic lethality will be examined similarly by constructing dose-lethality curves for each vasoconstrictor versus the approximate LD50 of each local anesthetic. The data obtained in this investigation are expected to help reconcile the conflict in the literature regarding the effects of epinephrine on local anesthetic toxicity as well as to add new information with respect to similar effects of levonordefrin. This study should also provide guidelines for designing more detailed experiments directed toward determining the mechanism of any differences observed. Such studies should provide a better understanding of the nature of the systemic interaction of vasoconstrictors with local anesthetic agents.